Cardiopulmonary Side Effects Research Articles

Sparing of the Heart Facilitates Recovery From Cardiopulmonary Side Effects After Thoracic Irradiation

IntroductionWhen irradiating thoracic tumors, dose to the heart or lung has been associated with survival. We previously showed in a rat model that in addition to known side-effects such as pericarditis, pneumonitis and fibrosis, heart and/or lung irradiation also impaired diastolic function and increased pulmonary artery pressure. Simultaneous irradiation of both organs strongly intensified these effects. However, the long-term consequences of this interactions are not yet known. Therefore, here we investigate the long-term effects of combined heart and lung irradiation. Material and MethodsDifferent regions of the rat thorax containing the heart and/or 50% of the lungs were irradiated with protons. Respiratory rate (RR) was measured bi-weekly as an overall parameter for cardiopulmonary function. Echocardiography of the heart was performed at 8, 26 and 42 weeks after irradiation. Tissue remodeling and vascular changes were assessed using Masson Trichrome and Verhoeff-stained lung and LV tissue collected at 8 and 42 weeks after irradiation. ResultsDuring the entire experimental period RR was consistently increased after combined heart/lung irradiation. This coincided with persistent effects on lung vasculature and reduced right ventricle contraction. In contrast, recovery of RR, pulmonary remodeling and right ventricle contraction was observed after sparing of the heart. These corresponding temporal patterns suggest that the reduction of right ventricle (RV) function is related to vascular remodeling in the lung. ConclusionCombined irradiation of lung and heart leads to an intensified, persistent reduction of cardiopulmonary function. Recovery of the pulmonary vasculature and right ventricle function requires heart-sparing.

2670: Captopril mitigates radiation-induced cardiopulmonary side effects only if the lung is spared

2670: Captopril mitigates radiation-induced cardiopulmonary side effects only if the lung is spared

Efficacy of Low-dose Ketamine for Control of Acute Pain in the Emergency Setting: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Ketamine can be particularly helpful in situations where the clinician is not able to administer opioids and require an alternate analgesic, such as for patients who are already on high-dose opioids, have a history of addiction, or for opioid-naïve children and adults. In this review, our goal was to obtain a comprehensive estimate of the efficacy and safety of low-dose ketamine (dose less than 0.5 milligrams per kilogram or equivalent) compared to opiates for the control of acute pain in the emergency setting. We conducted systematic searches in PubMed Central, EMBASE, MEDLINE, the Cochrane Library, ScienceDirect, and Google Scholar from inception until November 2021. We used the Cochrane risk-of-bias tool to assess the quality of included studies. We carried out a meta-analysis with a random-effects model and reported pooled standardized mean difference (SMD) and risk ratio (RR) with 95% confidence intervals depending on the type of the outcome. We analyzed a total of 15 studies with 1,613 participants. Half of them had high risk of bias and were conducted in the United States of America. The pooled SMD for pain score was -0.12 (95% CI -0.50-0.25; I2=68.8%) within 15 minutes, -0.45 (95% CI -0.84--0.07; I2=83.3%) within 30 minutes, -0.05 (95% CI -0.41-0.31; I2=86.9%) within 45 minutes, -0.07 (95% CI -0.41-0.26; I2=82%) within 60 minutes, and after 60 minutes the pooled SMD was 0.17 (95% CI -0.07-0.42; I2=64.8%). The pooled RR for need of rescue analgesics was 1.35 (95% CI 0.73-2.50; I2=82.2%). The pooled RRs were as follows: 1.18 (95% CI 0.76-1.84; I2=28.3%) for gastrointestinal side effects; 1.41 (95% CI 0.96-2.06; I2=29.7%) for neurological side effects; 2.83 (95% CI 0.98-8.18; I2=47%) for psychological side effects; and 0.58 (95% CI 0.23-1.48; I2=36.1%) for cardiopulmonary side effects. Low-dose ketamine might have higher or equivalent efficacy and safety when compared to opioids for managing acute pain among patients presenting to the emergency setting. However, further studies are required to establish conclusive evidence, owing to the heterogeneity and poor quality of existing studies.

Anesthesia, Coming of Age in the World of Modern In Silico Drug Design.

Anesthesia, Coming of Age in the World of Modern In Silico Drug Design.

ACUTE PULMONARY HYPERTENSION AFTER BORTEZOMIB THERAPY

ACUTE PULMONARY HYPERTENSION AFTER BORTEZOMIB THERAPY

Comparison of a new gasless method and the conventional CO2 pneumoperitoneum method in laparoendoscopic single-site cholecystectomy: a prospective randomized clinical trial

To avoid CO2 pneumoperitoneum-associated cardiopulmonary side-effects during conventional laparoscopic surgeries, we have developed a gasless laparoscopic operation field formation (LOFF) device for laparoendoscopic single-site surgery. The aim of this study is to analyze the safety and efficacy of the LOFF device for laparoendoscopic single-site cholecystectomy and to verify its advantage of avoiding CO2 pneumoperitoneum-associated complications. In this prospective, randomized, observer-blinded clinical trial, eligible participants were randomized in a 1:1 ratio to undergo either conventional CO2 pneumoperitoneum assisted laparoendoscopic single-site cholecystectomy (LESS) or the new gasless LOFF device assisted laparoendoscopic single-site cholecystectomy (LOFF-LESS). Outcomes including intra-operative respiratory and hemodynamic parameters, operation time, conversion rate, complication rate, et al were compared between the two groups. A total of 100 patients were randomized to the LESS group [n = 50; mean (SD) age, 49.5 (13.9) years; 24 (48.0%) women] and the LOFF-LESS group [n = 50, mean (SD) age, 47.4 (13.3) years; 27 (54.0%) women]. Compared with the LOFF-LESS group, the LESS group witnessed significant fluctuations in intra-operative respiratory and hemodynamic parameters. The tracheal extubation time of the LESS group was significantly longer (P = 0.001). The gasless LOFF device is safe and feasible for simple laparoscopic cholecystectomy and has a predominance of avoiding CO2 pneumoperitoneum-associated cardiopulmonary side-effects. Trial registration number: ChiCTR2000033702Graphic abstract

Fenfluramine for treatment-resistant epilepsy in Dravet syndrome and other genetically mediated epilepsies.

Fenfluramine hydrochloride, initially utilized as a weight loss drug in the 1970s and later removed from the market for adverse cardiopulmonary side effects, has since been repurposed as an antiseizure medicine (ASM). The potential antiseizure effects of fenfluramine were first identified in patients with photosensitive epilepsy in the 1980s but it was not rigorously explored as a treatment option until 30 years later. Compared with other ASMs, fenfluramine offers a novel mechanism by acting on serotonin and σ1 receptors, demonstrated in vitro and in vivo in animal models of Dravet syndrome. Results from a large double-blind, placebo-controlled trial demonstrated robust efficacy for seizure reduction in patients with Dravet syndrome, and met its primary endpoint with the 0.7 mg/kg/day fenfluramine treatment group experiencing a 62.3% or greater reduction in mean monthly convulsive seizure frequency (MCSF) compared with placebo. Here we provide a comprehensive review of the preclinical and clinical activity of fenfluramine, a recently approved drug for treatment of epilepsy in patients with Dravet syndrome.

Safety of Propofol in Cirrhotic Patients Undergoing Upper Endoscopy (EGD): A Systematic Review and Meta-Analysis

Introduction: EGD is recommended for patients with cirrhosis for screening and surveillance of varices. Underlying encephalopathy and decreased liver clearance may cause cardiopulmonary adverse events and worsening of hepatic encephalopathy in cirrhotic patients undergoing procedural sedation. With increasing use of Propofol for endoscopic procedures, it is important to assess its safety in these patients. Our aim was to examine available studies to derive pooled rates for the safety and efficacy of Propofol in cirrhotic patients undergoing EGD. Methods: Electronic database search was conducted in Medline, Embase, Cochrane for eligible studies that compared safety profile of Propofol between cirrhotics and controls (no cirrhosis). Following outcomes were examined to evaluate the safety profile of propofol: cardiopulmonary adverse events, procedure time, time to recovery, dosage, and number connection test (NCT) to assess cognitive impairment. Pooled rates of variables were reported as Odds ratio (OR) with 95% confidence interval and heterogeneity was reported as I2 statistics. Results: A total of 7 studies were found eligible and analysis with a total of 723 patients. (cirrhosis: 509 and control: 215). Rate of adverse events related to cardiopulmonary system were numerically higher in patients with cirrhosis (15.5% vs 12.09%), however, this was not statistically significant (pooled OR 1.06, 95% CI: 0.65-1.74, p 0.44). There was no significant difference in procedure time in cirrhotics compared to controls (mean weighted difference 1.76 minutes, 95% CI -1.81 to 5.34, p 0.33). Mean NCT score before and after procedure in the cirrhosis group was 82.93 seconds and 76.66 seconds, respectively (p=0.003). Weighted mean difference in NCT scores between the cirrhotic and control group before and after procedure was 49.27 seconds and 43.68 seconds, respectively suggesting no significant change in NCT scores in patients with cirrhosis. Mean dosage of Propofol in cirrhotics compared to controls was 99.26mg to 100.28mg (p=0.97). There was no significant difference in recovery time between two groups (mean weighted difference 0.10 minutes, 95% CI: -0.91 to 1.12, p 0.84). Conclusion: This meta-analysis suggests that Propofol does not adversely affect cognitive scores or recovery time in cirrhosis compared to controls when used for EGD. The cardiopulmonary side effects were also similar in both groups. Therefore propofol can be used safely for procedural sedation in patients with cirrhosis undergoing EGD.Figure: CARDIOPULMONARY COMPLICATIONS.Figure: RECOVERY TIME.Figure: PROCEDURE TIME.

Immobilization of Asiatic Black Bears (Ursus thibetanus) with Medetomidine-Zolazepam-Tiletamine in South Korea

The Asiatic black bear ( Ursus thibetanus ; ABB) is a globally endangered species for which a restoration program has been ongoing in South Korea since 2001. However, there is little information on immobilization protocols for ABBs. We evaluated the use of medetomidine-zolazepam-tiletamine for their immobilization. During 2005-13, we anesthetized 60 ABBs (32 males, 28 females; 7 mo to 12 yr old) with medetomidine 0.03-0.045 mg/kg and zolazepam-tiletamine 1.54-2.3 mg/kg; reversal of anesthesia was done with atipamezole 0.15-0.225 mg/kg administered intravenously alone or intravenously and intramuscularly (50:50). Mean (and SD) for physiologic collected for 373 immobilizations of at least 60 min were: time to sedation, 7.8 (5.4) min; anesthesia induction time, 13.7 (8.1) min; complete recovery time, 14.8 (12.4) min; respiratory rate, 14 (7) breaths/min; heart rate, 51 (16) beats/min; rectal temperature, 37.3 (1.3) C; and hemoglobin oxygen saturation, 88% (6%). Few cardiopulmonary side effects occurred during immobilization and adequate depth of anesthesia was maintained for >60 min without need for supplementation. The dosage and drug combination used was effective for immobilization of ABBs with minimal adverse effects on vital signs and can be recommended in most clinical applications.

CONTINUOUS INTRAVENOUS INFUSION ANESTHESIA WITH MEDETOMIDINE, KETAMINE, AND MIDAZOLAM AFTER INDUCTION WITH A COMBINATION OF ETORPHINE, MEDETOMIDINE, AND MIDAZOLAM OR WITH MEDETOMIDINE, KETAMINE, AND BUTORPHANOL IN IMPALA (AEPYCEROS MELAMPUS).

In order to develop a long-term anesthesia for flighty antelope species in field situations, two different protocols for induction and maintenance with an intravenous infusion were evaluated in wild-caught impala ( Aepyceros melampus ). Ten adult female impala were induced with two induction protocols: one consisted of 0.2 mg/kg medetomidine, 4 mg/kg ketamine, and 0.15 mg/kg butorphanol (MKB) and one consisted of 0.375 mg/kg etorphine, 0.2 mg/kg medetomidine, and 0.2 mg/kg midazolam (EMM). In both treatments, anesthesia was maintained with a continuous intravenous infusion (CII) at an initial dose rate of 1.2 μg/kg per hr medetomidine, 2.4 mg/kg per hr ketaminen and 36 μg/kg per hr midazolam. Partial reversal was achieved with naltrexone (2 : 1 mg butorphanol; 20 : 1 mg etorphine) and atipamezole (5 : 1 mg medetomidine). Evaluation of anesthesia included respiratory rate, heart rate, rectal temperature, arterial blood pressure, oxygen saturation, end tidal carbon dioxide tension, and tidal volume at 5-min intervals, palpebral reflex and response to painful stimuli at 15-min intervals, and arterial blood gases at 30-min intervals. Plasma cortisol concentration was determined after induction and before reversal. Duration and quality of induction and recovery were evaluated. EMM caused a faster induction of 9.5 ± 2.9 min compared to 11.0 ± 6.4 min in MKB. Recovery was also quicker in EMM (EMM: 6.3 ± 5.4 min; MKB: 9.8 ± 6.0 min). However, EMM also produced more cardiopulmonary side effects, including hypoxemia and hypercapnia, and calculated oxygenation indices (PaCO2-PETCO2) were worse than in MKB. One animal died after induction with EMM. The CII provided surgical anesthesia in 7 of 10 animals in MKB and in 9 of 9 animals in EMM for 120 min. In conclusion, the MKB induction protocol had advantages for prolonged anesthesia in impala with significantly less cardiopulmonary depression compared to EMM. The comparably decreased anesthetic depth could easily be adjusted by an increase of the CII.

Advances in molecular mechanism of cardioprotection induced by helium.

Helium has been classified as a kind of inert gas that is not effortless to spark chemical reactions with other substances in the past decades. Nevertheless, the cognition of scientists has gradually changed accompanied with a variety of studies revealing the potential molecular mechanism underlying organ-protection induced by helium. Especially, as a non-anesthetic gas which is deficient of relevant cardiopulmonary side effects, helium conditioning is recognized as an emerging and promising approach to exert favorable effects by mimicking the cardioprotection of anesthetic gases or xenon. In this review we will summarize advances in the underlying biological mechanisms and clinical applicability with regards to the cardioprotective effects of helium.

Dose-response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man.

CW002 is a benzylisoquinolinium nondepolarizing neuromuscular-blocking drug found to be inactivated by cysteine in preclinical studies. The current study represents a dose escalation clinical trial designed to describe CW002 potency, duration, cardiopulmonary side effects, and histamine release. Healthy subjects anesthetized with sevoflurane/nitrous oxide were divided into five groups (n = 6), each receiving a fixed CW002 dose (0.02, 0.04, 0.06, 0.08, or 0.10 mg/kg), and one group (n = 4) receiving 0.14 mg/kg. Blood pressure and heart rate were continuously recorded along with airway dynamic compliance. Neuromuscular blockade was assessed with mechanomyography at the adductor pollicis. Arterial blood was obtained before and after CW002 injection for analysis of plasma histamine concentration. Potency was estimated from a baseline sigmoid Emax model. ED50 was found to be 0.036 mg/kg (95% CI, 0.020 to 0.053 mg/kg) and ED95 0.077 mg/kg (95% CI, 0.044 to 0.114 mg/kg). At 0.14 mg/kg (1.8 × ED95), 80% twitch depression occurred in 94 ± 18 s with complete block in 200 ± 87 s. Clinical recovery (25% of maximum twitch) occurred in 34 ± 3.4 min, with a 5 to 95% recovery interval of 35.0 ± 2.7 min. The time to a train-of-four ratio greater than 0.9 ranged from 59 to 86 min. CW002 did not elicit histamine release or significant (greater than 10%) changes in blood pressure, heart rate, or dynamic airway compliance. In healthy subjects receiving sevoflurane/nitrous oxide, CW002 at 1.8 × estimated ED95 produces a clinical duration less than 40 min, elicits no histamine release, and has minimal cardiopulmonary side effects.

A comparison of propofol and midazolam/meperidine sedation in upper gastrointestinal endoscopy.

IntroductionThere is increasing interest in sedation for upper gastrointestinal endoscopy (UGE). Prospective randomized studies comparing sedation properties and complications of propofol and midazolam/meperidine in upper gastrointestinal endoscopy (UGE) are few.AimTo compare propofol and midazolam/meperidine sedation for UGE in terms of cardiopulmonary side effects, patient and endoscopist satisfaction and procedure-related times.Material and methodsThis was a prospective, randomized, double-blind study of propofol versus midazolam and meperidine in 100 patients scheduled for diagnostic upper gastrointestinal endoscopy. The patients were divided into propofol and midazolam/meperidine groups. Randomization was generated by a computer. Cardiopulmonary side effects (hypotension, bradycardia, hypoxemia), procedure-related times (endoscopy time, awake time, time to hospital discharge), and patient and endoscopist satisfaction were compared between groups.ResultsThere was no significant difference between the groups with respect to the cost, endoscopy time, or demographic and clinical characteristics of the patients. Awake time and time to hospital discharge were significantly shorter in the propofol group (6.58 ±4.72 vs. 9.32 ±4.26 min, p = 0.030 and 27.60 ±7.88 vs. 32.00 ±10.54 min, p = 0.019). Hypotension incidence was significantly higher in the propofol group (12% vs. 0%, p = 0.027). The patient and endoscopist satisfaction was better with propofol.ConclusionsPropofol may be preferred to midazolam/meperidine sedation, with a shorter awake and hospital discharge time and better patient and endoscopist satisfaction. However, hypotension risk should be considered with propofol, and careful evaluation is needed, particularly in cardiopulmonary disorders.

Long-Term Side Effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

Most patients with chronic myeloid leukemia have deep and durable responses when treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Imatinib (the first approved TKI), nilotinib, and dasatinib are used in newly diagnosed, relapsed or intolerant patients, while bosutinib and ponatinib are used only in relapsed or intolerant patients. Previously the drug of choice was related to the likelihood of response and, to a small extent, patient comorbidities. The long-term toxicities, particularly cardiopulmonary side effects, are now impacting treatment choice, making patient comorbidities of significant concern. About 10 % of patients do not tolerate their initial BCR-ABL1 TKI and an increasing number are developing long-term side effects, particularly with the second generation drugs. Side effects of the five drugs reviewed here highlight the differences between cardiovascular, pulmonary, gastrointestinal, and endocrine toxicities, as well as possible second malignancies. There is increasing evidence that patients whose disease is controlled by TKI's will have greater impact on their quality of life from comorbidities or drug adverse events than from the disease itself. Research into management of long-term toxicities is needed.

„Low-dose“-Droperidol-Gabe bei Kindern

Droperidol had been used as an effective antiemetic since the 1970s but was withdrawn from the market in 2001 because of a black box warning about QT prolongation and possible cardiac arrhythmia after high doses. In the meantime the black box warning has seriously been questioned and parenteral droperidol has again been licensed in 2008. Because droperidol acts on dopaminergic receptors different to 5-HT(3) antagonists and dexamethasone, it could possibly serve as a rescue drug after failed postoperative nausea and vomiting (PONV) prophylaxis. Persistent PONV after the recommended prophylaxis is a significant problem in pediatric anesthesia but a satisfactory strategy has not yet been defined. Therefore a retrospective audit was performed in order to evaluate whether low-dose droperidol (10 µg/kgBW) would be an effective rescue drug for failed antiemetic prophylaxis.The electronic anesthesia patient data base of the University Children's Hospital Zurich was searched from 2004-2009 for patients who received low-dose droperidol in the postanesthesia care unit as rescue therapy for persistent PONV after antiemetic prophylaxis. Based on the recorded electronic data the effectiveness of low-dose droperidol as PONV rescue therapy and possible side effects were analyzed.A total of 338 patients who received droperidol were found from a total of 34,032 patients and the charts were analyzed. Of these patients 134 were excluded because they had received droperidol for indications other than PONV, 43 patients were excluded because they had not received antiemetic prophylaxis before droperidol and in 17 patients the data were incomplete, leaving 144 patients with an average age of 12.3 years (interquartile range IQR 9.5-15.2 years) for analysis. The upper range of ages resulted from patients with chronic diseases who were still being treated in the Children's Hospital. Low-dose droperidol was given because of persistent nausea to 59 patients (41%) and to 85 patients (59%) for persistent vomiting. Initial antiemetic prophylaxis and/or therapy had consisted of dexamethasone plus tropisetrone in 80 patients and tropisetrone or dexamethasone alone in 64 patients. In 128 patients (89%) rescue therapy with a median dose of 10.9 µg/kgBW droperidol was effective but vomiting persisted in 16 patients (11%). Sedation was the only side effect recorded and this was observed in 39 patients (27%).Low-dose droperidol (10 µg/kgBW) was found to be effective as rescue medication in pediatric patients experiencing PONV despite various prophylactic antiemetic regimens. No neurological or cardiopulmonary side effects were recorded after this low dosage.

Comparison of xylazine-butorphanol and xylazine-morphine-ketamine infusions in horses undergoing a standing surgery

GENERAL anaesthesia presents a particularly high mortality and morbidity risk in horses (Johnston and others 2002). Several sedative protocols have been proposed for standing surgery in horses, all involving α2-adrenoreceptor...

Cardiopulmonary effects and safety of prostaglandin E1: A review

Intraarterial and intravenous infusion of prostaglandin E1 (PGE1) is established treatment for severe peripheral arterial occlusive disease, particularly in Europe and Japan. In this critical appraisal, experimental and clinical studies are reviewed, with special emphasis on cardiopulmonary effects and drug safety. The pulmonary data all indicate dose-dependent dilation of the pulmonary vessels with a reduction in pulmonary resistance. The known hemodynamic effects of PGE1 on the heart include an increase in stroke volume, cardiac index, and left ventricular ejection fraction, and a reduction in left ventricular filling pressure. Analysis of clinical trials shows a low rate of adverse effects, in particular a low incidence of cardiopulmonary side effects. If the recommendations for high-risk patients are observed, PGE1 is both an efficacious and safe therapeutic principle.

Propofol vs traditional sedative agents for endoscopic retrograde cholangiopancreatography: A meta-analysis

To investigate the efficacy and safety of propofol sedation for endoscopic retrograde cholangiopancreatography (ERCP). Databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials updated as of October 2010 were searched. Main outcome measures were ERCP procedure duration, recovery time, incidence of hypotension and hypoxia. Six trials with a total of 663 patients were included. The pooled mean difference in ERCP procedure duration between the propofol and traditional sedative agents was -8.05 (95% CI: -16.74 to 0.63), with no significant difference between the groups. The pooled mean difference in the recovery time was -18.69 (95% CI: -25.44 to -11.93), which showed a significant reduction with use of propofol sedation. Compared with traditional sedative agents, the pooled OR with propofol sedation for ERCP causing hypotension or hypoxia was 1.69 (95% CI: 0.82-3.50) and 0.90 (95% CI: 0.55-1.49), respectively, which indicated no significant difference between the groups. Propofol sedation during ERCP leads to shorter recovery time without an increase of cardiopulmonary side effects. Propofol sedation can provide adequate sedation during ERCP.

Diagnostic accuracy of modified transoesophageal echocardiography for pre-incision assessment of aortic atherosclerosis in cardiac surgery patients

BackgroundEpiaortic ultrasound scanning (EUS) is regarded as the reference standard for detecting atherosclerosis in the ascending aorta (AA). Combined with appropriate surgical modifications, EUS use can significantly reduce the incidence of postoperative stroke when detecting severe AA atherosclerosis. A recently introduced modification of conventional transoesophageal echocardiography (TOE), known as the A-View method, has proven capable of inspecting the distal AA. The objective of this study was to quantify the diagnostic accuracy of modified TOE in assessing atherosclerosis of the distal AA. MethodsAfter approval by the institutional medical ethical committee and after obtaining written informed consent, 465 consecutive patients above 65 yr old, undergoing elective cardiac surgery with a median sternotomy, were included. The study followed a cross-sectional diagnostic design. All consecutive patients underwent modified TOE followed by EUS (reference standard) to assess the severity of distal AA atherosclerosis. We constructed contingency tables to compare the presence (and severity) of atherosclerosis, detected by the two techniques. ResultsThe positive predictive value of modified TOE for the detection of clinically significant atherosclerosis was 67%, and the negative predictive value was 97%. The sensitivity was 95% and the specificity was 79%. One patient suffered a pulmonary haemorrhage, although he recovered without further sequelae. We did not observe any clinical significant haemodynamic or ventilatory effects. ConclusionsThe high negative predictive value and sensitivity show that modified TOE yields adequate diagnostic accuracy for excluding clinically relevant aorta atherosclerosis without significant cardiopulmonary side-effects, provided that the A-View catheter is introduced carefully.

Pharmacodynamics and Cardiopulmonary Side Effects of CW002, a Cysteine-reversible Neuromuscular Blocking Drug in Dogs

CW002 is a novel neuromuscular blocking drug with a duration dependent on the rate of cysteine adduction to the molecule. The current study characterized the pharmacodynamics and cardiopulmonary side effects of CW002 in dogs. In eight beagles, the dose required to produce 95% neuromuscular blockade (ED95) for CW002 was first determined and cysteine reversibility was confirmed. Five to 7 days later, incrementally larger doses were injected starting with 6.25 x ED95 and doubling the dose every 15 min. Before and after injection, blood was obtained for histamine analysis. Systemic and pulmonary arterial pressures, cardiac output, and left ventricular pressure and volume were recorded along with inspiratory pressure and pulmonary compliance. Ventricular contractility and lusitropy were indexed from pressure and volume data. The ED95 for CW002 from pooled data was 0.009 mg/kg. At 3 x ED95, onset time was 2.6 +/- 0.9 min and duration was 47 +/- 9 min. The duration was shortened to 3.7 +/- 0.6 min by 50 mg/kg L-cysteine injected 1 min after CW002. At 25 x ED95, CW002 reduced mean arterial pressure with concomitant decreases in systemic vascular resistance, mean pulmonary artery pressure, cardiac output, contractility, and lusitropy, beginning at 50 x ED95. However, even at a dose of 100 x ED95, the average change in any variable was less than 20%. There were no changes in pulmonary vascular resistance or ventilation mechanics at any dose, and histamine release occurred in only two of eight animals. CW002 is a potent neuromuscular blocking drug that at doses up to 100 x ED95 produces modest hemodynamic effects that are not associated with bronchoconstriction or consistent histamine release.